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© 1995 Oxford University Press

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Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNA Ser(UCN) gene

Valeria Tiranti1, Patrick Chariot1, Francesco Carella2, Antonio Toscano3, Paola Soliveri2, Paolo Girlanda3, Franco Carrara1, Giovanni Matteo Fratta4, Fiona M. Reid5, Caterina Mariotti1 and Massimo Zeviani1,*

1Division of Biochemistry & Genetics, National Neurological Institute ‘Carlo Besta’ Milan 21st Division of Neurology, National Neurological Institute ‘Carlo Besta’ Milan 3Neurological Clinic, State University School of Medicine Messina 4Division of Neurology, IRCCS-CSS San Giovanni Rotondo, Foggia, Italy 5Robertson Institute of Biotechnology, Faculty of Science, University of Glasgow Scotland, UK

*To whom correspondence should be addressed

Received April 20, 1995; Revised May 11, 1995; Accepted May 11, 1995

We report on a new maternally-inherited syndrome characterized by a combination of sensorineural hearing loss, ataxia and myoclonus in a large kindred from Sicily. Hearing loss was the most widespread and sometimes the only symptom found in family members. Sequence analysis of the mitochondrial DNA regions encompassing the tRNA genes revealed the presence of a heteroplasmic insertion at nucleotide position 7472. The insertion adds a seventh cytosine to a six-cytosine run that is part of the mitochondrial tRNA Ser(UCN) gene. Conformational analysis showed that this mutation is likely to alter the structure of the T{psi}C loop in the tRNA Ser(UCN) clover leaf secondary structure. Moreover, the degree of heteroplasmy in blood and muscle was correlated with the clinical phenotype, and homoplasmic mutant cybrids showed decreased complex I activity, low oxygen consumption and high lactic acid output, indicating faulty oxidative phosphorylation. Finally, mutation was absent in 381 unrelated maternal lineages, suggesting specific segregation with the disease. We propose that the C7472 insertion-mutation is pathogenic, and etiologically related to hearing loss and other symptoms that define a novel maternally-inherited clinical entity.


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